N-(benzocyclobutene-1-loweralkyl)-carboxylic acid amides



United States Patent Cfiice 3,398,157 l atented Mar. 7, 1967 B-CH-Am X/and acid addition salts thereof, in which Y and Z represent hydrogen,hydroxyl, lower alkoxy such as methoxy, ethoxy and propoxy, lowerthioalkyl such as thiomethyl and thioethyl, methylenedioxyandtrifiuoromethyl, R represents hydrogen, a lower alkyl such as methyl,ethyl and propyl, an aralkyl such as a phenyl-lower alkyl includingbenzyl and phenethyl, a cycloalkyl having 3 to 7 carbons in the ringincluding cyclopropyl, cyclopentyl and cyclohexyl, cycloalkyl-loweralkyl groups such as cyclopentylmethyl, cyclohexylethyl and other suchgroups in which the cycloalkyl has 3 to 7 carbons in the ring, R ishydrogen or a lower alkyl such as methyl, ethyl and propyl, B is asingle chemical bond or a straight or branched lower alkylene having upto 4 carbons in a chain such as methylene, ethylene, isopropylene andbutylene, and Am represents pyrrolidino, piperidino, morpholino, a4-lower alkyl-piperazino such as 4-methylpiperazino, a 4-(phenyl-loweraIkyD-piperazino such as 4-benzylpi-perazino, acylamino groups includingacetylamino, propion'ylamino, butyrylamino, benzoylamino,phenylacetylamino and 5-pyrrolidone-2-carboxyamino, and amino groups ofthe formula wherein R and R are selected from the list of groups for Ras well as aryl groups such as phenyl.

This invention uses as starting materials compounds of the formulaProbably the simplest compounds of this invention are the primaryamines. They can be produced by con vetting the nitrile group of thestarting materials to a methyleneamine group by reductive procedures.This reaction can be represented as follows:

B-CN B-OH2NH2 Z R. Z R1 in which B, R Y and Z have the assignedsignificance.

This reduction can be readily effected by chemical means, such as theuse of lithium aluminum hydride under anhydrous liquid reactionconditions. Anhydrous ether is a suitable reaction medium. Afterreacting the mixture, the intermediate complex can be decomposed as Withan aqueous alkali hydroxide solution. The ether layer can be decantedand dried with K CO and the product collected by distillation or theproduct can be converted into an acid addition salt and recovered assuch.

Some of the novel benzocyclobutene amines produced in this manner arel-aminomethyl-benzocyclobutene,

1- (Z-aminoethyl) -ben'zocyclobutene,

l- Z-aminopropyl -benzocyclobutene,1-aminornethyl-3-methyl-benzocyclobutene,

1-( 2-aminoethyl -6-methoxy-benzocyclobutene,

' l-aminomethyl-4,S-methylenedioxy-benzocyclobutene,

wherein B, R Y and Z have the significance previously assigned. Theprocess is especially suitable when acetic anhydride is used since itcan function as the solvent and leads to high yields of the desiredamine by forming the intermediate acetylate which suppresses sidereactions. The catalytic hydrogenation can be eifected at ambient orincreased temperatures using platinum oxide as the catalyst and hydrogenat moderate pressures of about 1 to 5 atmospheres. The intermediateacetyl amine can be separated by conventional means and then hydrolyzedas with hydrochloric acid to give the primary amme.

wherein E, R Y and Z have the significance previously assigned, X is areactive halo group such as the chloro or bromo groups and R ishydrogen, a lower alkyl such as methyl, ethyl and propyl, phenyl, aphenyl-lower alkyl such as benzyl and phenethyl, a cycloalkyl having 3to 7 canbons in the ring such as cyclopentyl and cyclohexyl,cycloalkyl-lower alkyl groups such as cyclopentylmethyl, cyclohexylethyland similar groups in which the cycloalkyl has 3 to 7 carbons in thering, and 2-(5-pyrrolido-ne). The reaction can be effected in an inertliquid reaction medium such as benzene, xylene, n-heptame and toluene.Approximately equimolar amounts of. reactants can be employed. Thereaction proceeds at room temperature although elevated temperaturessuch as the reflux temperature can be used to increase the reactionrate. An equivalent amount of an organic base such as triethylamine canbe included in the re action mixture to bind the hydrohalic acidreleased by the reaction. After the reaction is completed, whichgenerally takes no more than 1 to 3 hours, the reaction mixture can betreated according to conventional manipulative techniques to isolate thedesired product.

Some of the acyl halides of carboxylic acids which can be used in thisreaction are formyl chloride, acetyl chloride, propionyl chloride,butyryl chloride, isopropionyl bromide, caproyl chloride, benzoylchloride, phenylacetyl chloride, beta phenylpropionyl chloride,gamma-phenylbutyryl chloride, cyclopentane carboxyl chloride,cyclohexane carboxyl chloride, cyclopentyl acetyl chloride andbeta-cyclohexyl propionyl chloride.

Some of the benzocyclobutenyl amides formed in this way areN-acetyl-l-aminomethyl-benzocyclobutene,

N benzoyll- Z-aminoethyl -benzocyclobutene,N-cyclohexylacetyl-1-aminomethy1-3-trifluoromethylbenzocyclobutene, N-(1benzocyclobutenylmethyl)-5-oXo-2-pyrrolidinecarboxamide,N-acetyl-l-aminomethyl-l-methyl-benzocyclobutene, N-benzoyl- 1-(Z-arninoethyl l-benzyl-benzocyclobutene andN-cyclopentylacetyl-l-aminomethyl-l-cyclohexylmethyl-benzooyclobutene.

By routine hydrolysis the acyl groups of such amides can be cleaved toform the corresponding primary amines.

The amides can also be reduced to secondary amines with a reducing agentof which lithium aluminum hydride is preferred. This reaction can berepresented wherein B, R Y, Z and R have the significance previouslyassigned.

Secondary and tertiary amino benzocyclobutenes can also be produced byhydrolyzing a starting benzocyclobutenyl nitrile to the correspondingcarboxylic acid, reducing the acid to the alcohol, converting thealcohol to a sulfonate and reacting the sulfonate with an amine to formthe desired amine derivative of benzocyclobutene. This process can berepresented as follows:

2 H01 R Z 1 B-COOH wherein B, R Y, Z and Am have the significancepreviously assigned, but Am is not an acylamino group, and R is a loweralkyl such as methyl and ethyl or an aryl group such as phenyl andp-methylphenyl.

The first step of the rocess in which the nitrile group is hydrolyzed toa carboxylic acid group can be readily effected by reacting the nitrilewith an inorganic base, such as an alkali metal hydroxide, to convertthe nitrile group to a carboxylic acid salt which can then be treatedwith acid to form the free carboxyl group.

Some of the benzocyclobutenyl carboxylic acids which can be produced asdescribed are benzocyclobutene-l-carboxylic acid,

1- carb oxymethyl -benzocyclobutene,

1- (Z-carboxyethyl -1-methyl=benz ocyclobutene,

1- Z-carboxyisopropyl) 1-benzyl-benzoycyclobutene,

lcarboxymethyl -4-methoxy-be nzocyclobutene and 1- carboxymethyl-7-trifluoromethyl-benz0ycycl-obutene.

Reduction of the carboxyl group to the methylenehydroxy group is readilyeffected with lithium aluminum hydride in an anhydrous liquid reactionmedium such as ether or tetrahydrofur-an. An intermediate complexalcoholate forms which upon hydrolysis with acid yields the freealcohol.

Some of the benzocyclobutenyl alcohols which can be produced asdescribed are l-hydroXymethyl-benzocyclobutene,l-(Z-hydroxyethyl)-benzocyclobutene,l-hydroxymethyl-1-benzyl-benzocyclobutene,l-hydroXymethyl-7-trifluoromethyl-benzocyclobutene andl-hydroxyisopropyl-l-ethyl-3-methoxy-benzocyclobutene.

The benzocyclobutenyl alcohols can be readily converted to sulfonates byreacting the alcohol with a sulfonyl halide under basic conditions.Ethylsulfonyl chloride and p-toluenesulfonyl chloride illustrate thesulfonyl halides which can be used. Pyridine is preferred as the basicreaction medium. The reaction proceeds at ambient temperatures althoughlower temperatures are suitable.

By reacting a benzocyclobutenyl sulfonate, produced as described, with aprimary or secondary amine the corresponding secondary and tertiaryamines of benzocyclobutene can be produced. Among the amine reactantswhich can be used are lower alkyl amines such as 5 methylamine,ethylamine, and propylamine, phenylamine, benzylamine, phenylethylamine,di-lower alkyl amines such as dimethylamine, diethylamine,dipropylamine, N-methyl-N-propyl amine, dicyclohexylamine,di-cyclopentylmethyl amine, pyrrolidine, piperidine, morpholine, 4-loweralkyl-piperazines such as 4-methylpiperazine and 4-ethylpiperazine, and4-phenyl-lower alkyl-piperazines such as 4-benzylpiperazine and4-(2phenylethyl)-piperazine.

Representative of the secondary and tertiary amines of benzocyclobutenewhich can be produced using this process are The secondary amines, andthe tertiary amines which are not cyclic, can also be produced byreacting a primary amine of cyclobenzobutene with an organic halide. Anexcess of the halide can be used to promote formation of the tertiaryamines and an excess of the primary amine can be used to promoteformation of the secondary amines. The formation of the secondary andtertiary amines can be illustrated as follows:

wherein B, Y, Z, R and R have the assigned significance and X is areactive halo group such as chloro and bromo.

Benzocyclobutene amines of the formula 1' 1 BOHNH:

wherein Y, Z, B, R and R have the assigned significance wherein X, Y, Z,B, R and R have the assigned signficance but R is not hydrogen.

The nitrile is reacted with a suitable Grignard reagent in the firststep and the ketimine salt so formed is hydrolyzed to form the acylbenzocyclobutene.

Some of the Grignard reagents which can be used aremethylmagnesiumbromide, phenylmagnesiumiodide, ethylmagnesiumchlorideand benzylmagnesiumbromide.

The Grignard reaction is readily effected employing conventionalconditions of solvent, temperature and the like. The complex ketiminesalt is readily hydrolyzed by adding a weak acid to the resultingreaction mixture. The product can be isolated and purified by standardprocedures.

Some of the acyl benzocyclobutenes formed in this Way are l-acetylbenzocyclobutene,

l-propionyl benzocyclobutene, l-acetonyl benzocyclobutene,1-phenylacetyl benzocyclobutene, l-acetyl-l-methyl benzocyclobutene and.1-propionyl-7 trifiuoromethyl benzocyclobutene.

, The acyl benzocylobutenes, such as those just described, are nextconverted to oximes by reaction with hydroxylamine, advisably in anorganic reaction medium in which the reactants are soluble. Thehydroxylamine can be produced in situ by the neutralization of ahydroxylamine salt such as the hydrochloride. Inorganic bases such asthe alkali metal hydroxides, carbonates and bicarbonates, as well asorganic bases such as pyridine, can be used to neutralize the acidreleased from the hydroxylamine salt.

Lower alcohols such as ethanol and isopropanol, as well as other organicsolvents in which the reactants are soluble, such as tetrahydrofuran,can be used as the reaction' medium. The reaction is promoted by the useof moderately elevated temperatures with the reflux temperature beingparticularly suitable. The reaction is substantially completed in about1 to 4 hours. After the reaction is terminated the reaction mixture canbe chilled 'with ice water, extracted With ether and the oily productcrystallized from a solvent such as cyclohexane.

Some of the l-acyl-benzocyclobutene oximes which can be prepared asdescribed are l-acetyl benzocyclobutene oxime,

l-propionyl benzocyclobutene oxime,

l-acetonyl benzocyclobutene oxime,

l-phenylacetyl benzocyclobutene oxime, l-acetyl-l-methylbenzocyclobutene oxime and 1-propiony1-7-trifluoromethylbenzocyclobutene oxime.

The oximes can be reduced to amines using lithium aluminum hydride atthe conditions herein described for other reductions with this agent.

Some of the amines that are produced from the oximes are l-(l-aminoethyl) -benzo cyclobutene,

1- Z-arninopropyl -benzocyclobutene,

1-( l-amin-opropyl) -benzoc-yclobutene,

l-( l-amino-Z-phenyl ethyl) -benzocyclobutene and 1-( l-aminoethyl)-1-rnethyl-benzocyclobutene.

Acid addition salts are produced by contacting the amines with asuitable acid such as formic acid, citric acid, maleic acid, sulfuricacid, hydrochloric acid, succinic acid, tartaric acid, benzoic acid orfumaric acid.

The amines and acyl derivatives provided herewith have sympath-ornimeticactivity. They exert central nervous system stimulation, analgeticactivity and skeletal muscle relaxant activity, in animals. Thecompounds also appear to be anorexogenics, analeptics, pressor agents,monoamine oxidase inhibitors, beta-oxidase inhibitors, and DOPAdecarboxylase inhibitors. Since the amines are basic they can be used asneutralizing agents and to form salts with penicillin for separating andpurifying this antibiotic.

The amines (including the acyl derivatives) of this invention may beadministered to animals and humans as pure compounds. It is advisable,however, to first combine one or more of the compounds with a suitablepharmaceutical carrier to attain a more satisfactory size to dosagerelationship.

Pharmaceutical carriers which are liquid. or solid may be used. Thepreferred liquid carrier is water, Flavoring materials may be includedin the solutions as desired.

Solid pharmaceutical carriers such as starch, sugar, talc and the likemay be used to form powders. The powders may be used as such for directadministration to a patient or, instead, the powders may be added tosuitable foods and liquids, including water, to facilitateadministration.

The powders may also be used to make tablets, or to fill gelatincapsules. Suitable lubricants like magnesium stearate, binders such asgelatin, and disintegrating agents like sodium carbonate in combinationwith citric acid may be used to form the tablets.

Unit dosage forms such as tablets and capsules may contain any suitablepredetermined amount of one or more of the active agents as a nontoxicacid addition salt and may be administered one or more at a time atregular intervals. Such unit dosage forms, however, should generallycontain a concentration of 0.1% to by weight of one or more of theactive agents. Unit dosage forms should advisably contain about 5 to 150mg. of the active agents described herein.

A typical tablet may have the composition:

Mg. (1) 1-aminomethyl-benzocyclobutene hydrochloride 1 (2) Starch U.S.P.57 (3) Lactose U.S.P. 73 (4) Talc U.S.P 9 (5) Stearic acid 6 Powders, 1,2 and 3 are slugged, then granulated, mixed with 4 and 5, and tableted.

Capsules may be prepared by filling No. 3 hard gelatin The oral route ispreferred for administering the active agents of this invention.However, other modes of administration, such as parenteral, may beemployed.

n 0 The starting nitriles of the formula wherein Y and Z have theassigned significance, can be produced by reacting the appropriatelynuclear substituted alpha-halo-O-halo toluene with ethyl cyanoacetate toform an ethyl Z-halobenzyl cyanoacetate, hydrol-yzing said compound toform 2-halobenzyl-cyanoacetic acid, heating said compound indimethylacetamide to form 3-(2-ha1ophenyl) -propiononitrile andcyclizing said compound with sodamide in liquid ammonia to forml-cyanobenzocyclobutene having on the phenyl group whatever nuclearsubstituents Y and Z that were there at the start of the process. Thisprocess can be represented as follows:

wherein Y and Z have the previously assigned meaning and A and A are thesame or different reactive halo groups such as the chloro and bromogroups. Publications relevant to these reactions are J. Org. Chem., 27,3836 (1962); J. Am. Chem. Soc., 80, 2257 (1958); and Canadian Journal ofResearch 28B, 352 (1950).

l-cyanoalkylene benzocyclobutenes can be built up a methylene at a timewith straight chain alkylenes accord ing to the following procedure TNaCN CHzOTS nHzCN CzHsOH LiAlHt CH2CO2C2H TSCI . "memoir Pyndme A NaCNLi CY CH2OTS H01 etc. "memoir CZHEOH wherein Y and Z have the assignedsignificance and Ts is the tosyl group.

The l-cyanoalkylene benzocyclobutenes in which the alkylene is branchedcan be prepared via the following process:

wherein Y, Z, B and Ts have the assigned meaning and R is a lower alkyl.The alkyl represented by R can be positioned at any point in the chainin this way with the location being determined by the starting nitrile.Once the branch is introduced thetosylate can be converted z z R1 inwhich Y, Z and R have the assigned significance but R is not hydrogenand X is a reactive halo group such as chloro or bromo. Organic halidessuch as methyl chloride, ethyl bromide, phenyl chloride, benzylchloride, Z-phenylethyl bromide, cyclopentyl chloride andcyclohexylmethyl chloride are representative reactants which can beused. The process can be effected in benzene in the presence of ahalogen acceptor, such as sodamide, at moderately elevated temperatures.Products such as those previously described and named herein can be produced in this way.

The following examples are presented to further illustrate theinvention:

Example 1.1-cyanobenzocycloburene (A) Ethyl2-chl0r0benzyl-cyan0acetate.To a solution of sodium (140 g.) in 4 litersof absolute ethanol was added 3043 g. of ethyl cyanoacetate at amoderate rate.

The milky solution was stirred for 1 hour, then was treated with 966 g.of alpha, ortho-dichlorotoluene over a 2 hour period with thetemperature kept below 30 C. After stirring for an hour, the solutionwas refluxed overnight. The solvent was removed by distillation and theorganic residue was taken up in ether (1 liter). The ethereal solutionwas extracted with 1 liter of water which was separated and shaken with500 ml. of ether. The combined ether portions Were dried over anhydroussodium sulfate and evaporated. The excess ethyl cyanoacetate wasdistilled, and the residue was fractionated to give the monobenzylatedcyanoester, B.P. 117 123 C. at 0.025 rnm.

Analysis.Calcd. for C H ClNO N, 14.93. Found: N, 14.92.

(B) Z-chlorobenzyl-cyanoacetic acid.-Ethyl 2-ch1orobenzyl-cyanoacetate(890 g.) was added to 2 liters of 10% aqueous sodium hydroxide kept at25 C. by external cooling. The solution was stirred an additional 20min. and, with continual cooling, was acidified with 525 ml. ofconcentrated hydrochloric acid. The colorless, crystalline precipitatewas filtered, washed repeatedly with water and dried to afford thecyanoacid, M.P. 129-132 C.

Analysis-Gabi for C H ClNO: N, 6.68; Neut. equi., 209.6. Found: N, 6.65;Neut. equi., 212.2.

(C) 3-(Z-chlorophenyl)-propi0nonitrile.-A solution of2chlorobenzyl-cyanoacetic acid (750 g.) in 750 ml. of dimethylacetamidewas kept within a temperature range of l35--155 C. for 2 hours. Nitrogenwas bubbled through the solution during this time. On cooling, thesolution was poured into 2 liters of water; the organic phase was takenup in ether, which was separated and dried over anhydrous sodiumsulfate. The liquid that remained on removal of the solvent wasdistilled to afford the nitrile, B.P. 86-87 C. at 0.05

(D) 1-cyan0benz0cycl0butene.3-(2 chlorophenyl)- propiononitrile (67.5g.) was allowed to react with 65 g. of sodium amide in 1.6 liters ofliquid ammonia for 4 hours. The reaction mixture was neutralized withammonium nitrate and the ammonia was allowed to evaporate. Water wasadded cautiously to the residue. The crude product was taken up in etherwhich was dried over anhydrous sodium sulfate. The product wasevaporated and the remaining liquid was distilled to give the bicyclicnitrile, B.P. 66-67 C. at 0.2 mm.

Example 2.-1-cyan0?5-m'eth0xy-benz0cycl0butene (A) Ethyl2-br0lmo-4-methoxybenzyl-cyan0acetate. Ethyl cyanoacetate andalpha-chloro-ortho-bromo-para methoxy toluene were reacted as in Example1A to form ethyl 2-bro-mo-4-methoxybenzyl cyanoacetate; B.P. 148- 151 C.(0.05 mm.).

Analysis.Calcd. for C H BrNO C, 50.01; H, 4.52; N, 4.49. Found: C,50.11; H, 4.56; N, 4.37.

(B) 2-brom0 4 methoxybenzyl cyanoacetfc acid- Ethyl2-bromo-4-m-ethoxybenzyl-cyanoacetate was hydrolyzed as in Example IE toform 2-brorno-4-methoxybenzyl-cyanoacetic acid; M.P. 114.5147.5 C. afterrecrystallization from benzene.

Analysis.Calcd. for C H BrNO C, 46.50; H, 3.59; N, 4.93; Neut. equi.,284.12. Found: C, 46.38; H, 3.29; N, 4.98; Neut. equi., 281.14.

(C) 3- (2-br0m 0-4-meth0xyg7henyl) -propiononitrile.2-bromo-4-methoxybenzyl-cyanoacetic acid was reacted withdimethylacetamide as in Example 10 to give 3-(2-bromo-4-methoxyphenyl)-propiononitrile; B.P., -120 C. (0.15 mm.).

Analysis.Calcd. .for C H BrNO: C, 50.02; H, 4.20; N, 5.84. Found: C,50.08; H, 4.12; N, 5.74.

(D) J-cyano 5 meth0xybenz0cycl0-butene.3 (2- bromo 4 methoxyphenyl)propiononitrile and sodium amide were reacted in liquid ammonia as inExample 1D to give 1-cyano-5-methoxybenzocyclobutene, B.P. 122 C. (0.25mm.).

Analysis.Calcd. for C H NO: C, 75.44; H, 5.70; N, 8.80. Found: C, 75.19;H, 5.52; N, 8.78.

Example 3.-N-acetyl-1-aminometlzyl-benzocyclobatenel-cyanobenzocyclobutene (12.9 g.) and 0.15 g. of platinum oxide in 50ml. of acetic anhydride were treated with hydrogen at room temperatureand an initial pressure of 3.3 atmospheres. The hydrogen uptake wascomplete after 32 hours. The catalyst was removed by filtration. Thefiltrate was poured into 300 g. of ice water which then was saturatedwith sodium bicarbonate. The organic layer was taken up in ether whichwas dried and evaporated. Distillation of the residue afforded theproduct as a colorless, viscous liquid, B.P. 150-154 C. at 0.5 mm.

Analysis.-Calcd. for C H NO: C, 75.39; H, 7.47; N, 7.99. Found: C,75.52; H, 7.83; N, 8.15.

Example 4.-1-amin0methyl-benzocyclobutene hydrochlorideN-acetyl-l-aminomethyl-benzocyclobutene (11 g.) in 20% hydrochloric acid(40 .ml.) was refluxed for 3.5 hours. The solution was diluted withwater, filtered and evaporated to dryness. Recrystallization of thesolid residue from aqueous ethanol gave the salt as white plates, M.P.213215 C.

Analysis.Calcd. for C I-I ClN: Cl, 20.89; N, 8.26. Found: Cl, 21.02; N,8.32.

Example 5.N-methyl-1-amin0methyl-benzocyclobutene HCl (A)Benzocyclobatene I carboxylic acid.1-cyanobenzocyclobutene (53 g.) washydrolyzed to the corresponding acid by the method of Cava and Mitchellin J. Org. Chem. 27, 631 (1962). After recrystallization from n-hexane,the acid had a M.P. of 72.574 C.

(B) 1-hydroxymethyl-benzocyclobutene.Benzocyclobutene-l-carboxylic acid(71 g.) was reduced with lithium aluminum hydride to the primary alcoholby the procedure of Cava and Mitchell in J. Org. Chem. 27, 631 (1962).The product had a B.P. of 70 C. at 0.5 mm.

(C) J-hydroxymethyl benzocyclobutene tsylate.-A solution of tosylchloride (76.2 g.) in 150 ml. of pyridine was added over a hour periodto a solution of 1-hydroxymethyl-benzocyclobutene (46.9 g.) in 100 ml.of pyridine kept between 010 C. The orange colored mixture was stirredan additional 16 hours with cooling, then was poured into 1000 ml. ofice water. The separated oil was taken up in 1 liter of ether, which wasWashed several times with 250 ml. portions of 2 N sulfuric acid, oncewith 5% sodium bicarbonate (300 ml.) and finally with water. Evaporationof the dried solvent gave an oil which solidified on refrigeration undernhexane. The pale yellow solid melted at 5257 C.

Analysis.Calcd. for C O O S: C, 66.64; H, 5.59; S, 11.12. Found: C,66.77; H, 5.63; S, 10.93.

(D) N methyl 1 aminomethyl benzocyclobutene HCl.A solution of1-hydroxymethyl-benzocyclobutene tosylate (17.3 g.) in 125 ml. ofbenzene saturated at C. with monomethylamine was heated in an autoclaveat 100 C. for 24 hours. The cooled mixture was washed with dilute sodiumbicarbonate, then with water and was dried over anhydrous sodiumsulfate. The liquid remaining after solvent evaporation was dissolved inanhydrous ether and was treated with dry hydrogen chloride. Theresulting salt melted at 192-194 C. after recrystalllization fromisopropyl alcohol.

Analysis.Calcd. for C H ClN: Cl, 19.30; N, 7.63. Found: Cl, 19.37; N,7.59.

Example 6.N,N-dimcthyl 1-aminomethyl-benzocyclobutene maleate The amine(Example 5C) was prepared from 14.4 g. of1-hydroxymethy1-benzocyclobutene tosylate and 100 m1. of dimethylaminesaturated benzene by the same procedure followed for the monomethylcompound of Example 5D. The salt crystallized from 2-propanol ascolorless plates, M.P. 116118 C.

12 Analysis.-Calcd. for C H NO C, 64.97; H, 6.90; N, 5.05. Found: C,65.17; H, 6.94; N, 5.05.

Example 7.1-(1-benz0cyclabutenylmethylene)- morpholine HCl A solution of1-hydroxymethyl-benzocyclobutene tosylate 10.1 g.) and 8.7 g. ofmorpholine in 40 ml. of toluene was refluxed for 20 hours undernitrogen. The mixture was filtered of the precipitated salt and thefiltrate evaporate-d to dryness. The residual oil was taken up in etherwhich was washed thoroughly with water, dried and evaporated. Theremaining straw-colored liquid was allowed to react with dry hydrogenchloride in anhydrous ether. The white salt melted at 217.5-219 C. afterrecrystallization from 2-propanol.

Analysis.CalCd. for C H ClNO: Cl, 14.79; N, 5.84. Found: Cl, 14.66;N,5.81.

Example 8.1-aminomethyl-5-meth0xybenz0cycl0- butane HCl A coldsuspension of lithium aluminum hydride (2.88 g.) in 150 ml. of anhydrousether was treated dropwise with a solution of1-cyano-5-methoxybenzocyclobutene (9.6 g.) in 100 ml. of ether. Afterthe addition was complete, the mixture was refluxed for 3 hours and thenwas stirred at room temperature for another 12 hours. The reaction wasquenched by the careful introduction of water (25 ml.). After theaddition of 30 ml. of 1% aqueous sodium hydroxide, the ether phase wasseparated, dried and evaporated. Distillation of the residual materialgave a colorless liquid, B.P. 91-106 C. at 1 mm. An ethereal solution ofthe amine was treated with dry hydrogen chloride to afford a white,crystalline solid, M.P. 162-163 C. after recrystallization fromisopropyl alcohol.

Analysis.-Calcd. for C H ClNO: C, 60.16; H, 7.06; Cl, 17.75; N, 7.02.Found: C, 59.97; H, 7.25; C1, 17.98; N, 7.15.

Example 9.1-amin0methyl-I-benzyl-benzocycl0- butene HCl (A) 1 -berzzyl-1-cyano benzocycl0butene.-A solution of 1-cyano-benzocyclobutene (25.8g.) and benzyl chloride (26.6 g.) in 200 ml. of dry benzene was treatedportionwise with 7.8 g. of sodium amide. The temperature was kept below40 C. during the addition. The well-stirred mixture was heated to C. andwas kept at that temperature for 4 hours. Water ml.) was added, thebenzene layer was separated and dried over anhydrous sodium sulfate.Solvent evaporation afforded an amber liquid which was distilled. Theproduct, a colorless, viscous liquid, boiled at 118-122" C. (0.01 mm.).

Analysis.-Calcd. for C H N: C, 87.64; H, 5.97; N, 6.39. Found: C, 87.28;H, 6.20; N, 6.41.

(B) 1 -aminomethyl-1 -benzyl-benzocyclobutene HCl. A solution ofl-benzyl-l-cyanobenzocyclobutene (11 g.) in 100 m1. of anhydrous etherwas added slowly to a cold suspension of lithium aluminum hydride (5.7g.) in ml. of dry ether. Following the addition, the mixture wasrefluxed for 9 hours; then the excess reagent was decomposed carefullywith water. Evaporation of the dried ether solution afforded the amineas a clear, colorless liquid. It was redissolved in anhydrous ether andtreated with dry hydrogen chloride. The amine salt was obtained as awhite, crystalline solid on recrystallization from absolute ethanol,M.P. 220221.5 C.

Analysis.-Calcd. for C H CIN: Cl, 13.64; N, 5.37. Found: Cl, 13.64; N,5.36.

Example 10.1-(1-amin0ethyl)-benz0cyclobutene HCl (A) l-acetylbenz0cycl0butene.To the Grignard reagent prepared from 5.8 g. ofmagnesium and 31.5 g. of methyl iodide was added with refluxing 25.8 g.of l-cyanobenzocyclobutene in 100 ml. of ether. The mixture was heatedfor 5 hours and then was cooled; the complex was decomposed withsaturated ammonium chloride solution.

13 Evaporation of the dried ether solution gave a viscous liquid whichwas heated in 100 ml. of water at 80 C. for 1 hour. The organic phasewas taken up in ether which was dried and evaporated. Distillation ofthe residue gave the ketone as a colorless liquid, B.P. 93-103 C. at 3.5mm.

(B) I-acetyl benzocyclobutene oxime.To a cold solution of 2.4 g. ofhydroxylamine hydrochloride and 2.8 g. of sodium acetate in 80 ml. of50% aqueous ethanol was added dropwise 4.7 g. ofl-acetylbenzocyclobutene in 15 ml. of ethanol. The solution was stirredin an ice bath for 2 hours, at room temperature for 12 hours and finallyit was refluxed for 1 hour. Solvent evaporation gave an oil whichcrystallized on cooling. Recrystallization from n-hexane afforded theoxime as a colorless solid, M.P. 9091.5 C.

Analysis.Calcd. for C H NO: C, 74.53; H, 6.88; N, 8.29. Found: C, 74.32;H, 6.82; N, 8.57.

(C) l-(l-aminoethyl)-benzcycl0butene HCl.--A solution of l-acetylbenzocyclobutene oxime (7.7 g.) in 200 ml. of anhydrous ether was addedover a l-hour period to a suspension of lithium aluminum hydride (4 g.)in 200 ml. of ether. The reaction mixture was stirred at roomtemperature for 24 hours and then was treated carefully with 25 ml. ofwater. The oily residue from evaporation of the dried ether solution wasallowed to react with ethereal hydrogen chloride. Recrystallization ofthe precipitated white solid from isopropyl alcohol aiforded the aminesalt, M.P. 212213 C.

Analysis.Calcd. for C H ClN: Cl, 19.30; N, 7.63. Found: Cl, 19.43; N,7.51.

Example 11.N-(1-benzocyclobutenylmethyl) --0x0-2-pyrrolidinecarboxam'ide A solution of 5-oxo-2-pyrrolidinecarboxylicacid (1.55 g.) and triethylamine (1.2 g.) in 40 ml. of dichloromethanewas cooled to 4 C., and ethyl chloroformate (1.3 g.) in 15 ml. ofdichloromethane was added dropwise with stirring. After 1 hour a mixtureof l-aminomethyl-benzocyclobutene hydrochloride (2 g.) and triethylamine(1.2 g.) in 75 ml. of dichloromethane was added. The reaction mixturewas stirred at room temperature for 18 hours. The organic phase wasextracted with water and with 5% sodium bicarbonate and was dried overanhydrous sodium sulfate. Crystallization of the oily residue obtainedon solvent evaporation from chloroform-n-hexane afforded a solid, M.P.99106 C.

in which B is lower alkylene and R is lower alkyl.

2. N-acetyl-l-aminoethyl-benzocyclobutene. 3. A compound of the formulain which B is lower alkylene and R is a member of the group consistingof hydrogen, lower alkyl, phenyl, phenyllower alkyl, cycloalkyl having 3to 7 carbons in the ring, cycloalkyl-lower alkyl having 3 to 7 carbonsin the ring and 2-(5-pyrrolidone), and Y and Z are hydrogen, hydroxy,lower alkoxy, methylenedioxy or trifluoromethyl.

References Cited by the Examiner UNITED STATES PATENTS 1,915,334 6/ 1933Salzberg et al 260243 2,075,359 3/1937 Salzberg et al. 16722 2,362,61411/1944 Calva 16722 3,051,722 8/ 1962 Biel 260-2472 OTHER REFERENCESBlomquist et al.: Ann., vol. 653, pages 67-79, 1962, only page 71.

Cava et al.: J. Am. Chem. Soc., vol. 80, 1958, pages 2257-2263, onlypage 2260 relied on.

ALEX MAZEL, Primary Examiner.

HENRY R. JILES, Examiner JOSE TOVAR, Assistant Examiner.

Notice of Adverse Decision in Interference In Interference No. 96,856involving Patent No. 3,308,157, J. E. Robertson and J. A. Skorcz, N-(BENZOCYCLOBUTENE-1LOWERALKYL)-CAR- BOXYLIC ACID AMIDES, final judgmentadverse to the patentees was rendered Mar. 31, 1972, as to claim 2.

[Oyfioial Gazette August 22,1972.

2. N-ACETYL-1-AMINOETHYL-BENZOCYCLOBUTENE.
 3. A COMPOUND OF THE FORMULA